University of Groningen
The impact of albuminuria and cardiovascular risk factors on renal function
Verhave, Jacoba Catharijne
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Chapter 8
An elevated urinary albumin excretion predicts de novo
development of renal function impairment in the general
population
Jacobien C. Verhave, Ron T. Gansevoort, Hans L. Hillege, Stephan J.L. Bakker,
Dick de Zeeuw, Paul E. de Jong
Kidney International 2004;66 Suppl 92:S1-S4
110
Chapter 8
Abstract
Objectives
We questioned which factors determine the risk for developing renal function impairment.
Methods
To that purpose we studied the incidence of newly diagnosed impaired renal function (GFR <
60 mL/min/1.73 m2) in the PREVEND cohort (n= 8,592), which is enriched for the presence
of albuminuria, and which was first studied in 1997/98.
Results
Of this cohort 6,894 subjects were studied again 4 years later. Subjects with known renal
disease, GFR < 60 mL/min, missing GFR values or sediment abnormalities at the first
screening were excluded from the present analysis (n= 872). We examined whether
albuminuria is associated with the de novo development of an impaired renal function. GFR
was 90.3 (SD 16.3) mL/min/1.73 m2 at baseline and 11.6% of the subjects had an albuminuria
of more than 30 mg/day. After a follow up of 4 years, 253 subjects (4.2%) were found to
have a GFR < 60 mL/min/1.73 m2. The subjects with newly diagnosed impaired GFR were
older, had a higher blood pressure, serum cholesterol, plasma glucose and urinary albumin
excretion at the first examination, and had a lower GFR to start with than those with a GFR >
60 at the second evaluation. Subjects with de novo impaired GFR had a comparable BMI and
smoked less frequently compared to subjects with GFR > 60. In multivariate analysis urinary
albumin excretion was independently predictive for the risk to develop an impaired GFR (p=
0.001).
Conclusions
In the general population measurement of urinary albumin excretion may prove to be a
valuable tool to detect subjects at risk for later development of renal failure, independent of
the presence of other cardiovascular risk factors.
Keywords
Renal function, Cockcroft-Gault, MDRD, urinary albumin excretion, PREVEND.
Albuminuria and impaired renal function
111
Introduction
Urinary albumin excretion (UAE) is a predictor of renal function impairment in diabetic
subjects. Patients with type 1 diabetes frequently have an elevated glomerular filtration rate
(GFR) the first decade after the diagnosis of the diabetes. In that period UAE gradually
increases to the level of microalbuminuria (30-300 mg/24h). In subsequent years the risk for
developing overt nephropathy and progressive renal failure is particularly high for those with
microalbuminuria (1). This elevated UAE is not only a renal risk marker but also a
cardiovascular risk marker in diabetes (2-4). In the general population albuminuria has also
been proven to be of predictive value as marker for increased cardiovascular morbidity and
mortality (5-7). However, longitudinal data on the predictive value of albuminuria for renal
morbidity and mortality are thus far limited to diabetes. In the present study we therefore
aimed to study the association of albuminuria at baseline and the de novo renal function
impairment after four years follow-up in apparently healthy subjects.
Material and Methods
Study design and population
The PREVEND (Prevention of Renal and Vascular End-stage Disease) study was initiated in
1997 with the aim to investigate the impact of urinary albumin excretion on renal and
cardiovascular disease in the general population (8). A cohort drawn from the city of
Groningen, the Netherlands, (28-75 years) with an oversampling of subjects with an elevated
urinary albumin concentration, was screened during two visits at the outpatient clinic.
Pregnancy and insulin use were exclusion criteria. Overall 8,592 subjects were included. After
a mean follow-up of 4.2 year (range 2.8-6.1) the participants were invited for identical visits
to the outpatient clinic. Of the overall cohort 6,894 subjects were seen for the second
screening. Subjects with known renal disease (n= 47), a GFR < 60 mL/min/1.73 m2 (n= 336)
or urinary sediment abnormalities (leukocytes > 75 /µl or erythrocytes > 50 erythrocytes /µl,
or leukocytes = 75 and erythrocytes > 5 /µl) (n= 316) were excluded. In addition, 173 subjects
were excluded because of missing data, leaving 6,022 subjects for the present analysis. Renal
function was calculated by the Cockcroft-Gault formula (9) and by the MDRD formula (10).
The Cockcroft-Gault formula was corrected for body surface area (BSA), the MDRD formula
is per definition corrected for standard body surface area. Urinary albumin excretion is given
as the mean of two 24 hour urine excretions. Impaired renal function was defined as GFR <
60 mL/min/1.73 m2 (11).
At the initial visit serum creatinine was determined by Kodak Ektachem dry chemistry
(Eastman Kodak, Rochester, NY, USA) and during follow-up by photometric determination
with the Jaffé method without deproteinisation (Merck KGaA, Darmstadt, Germany). To
check whether this change in analytical method may influence results, serum samples were
obtained of 200 subjects, known to have serum creatinine values evenly distributed over a
range from 45 to 145 µmol/L. In these samples creatinine was measured simultaneously with
both methods. Linear regression analysis was performed using the procedure proposed by
Passing and Bablok (12,13). It appeared that serum creatinine measured by photometric
determination was in general higher. To correct for this systematic bias a correction formula
was introduced: Creatinine corrected = 1.027 X - 8.243, where X is serum creatinine
measured by photometric determination.
112
Chapter 8
Statistical analyses
Comparison of the population characteristics at baseline for normal versus impaired renal
function at follow-up were tested for continuous variables by a Student t-test, for categorical
variables by a Chi-square test and for UAE, because of its skewed distribution, by KruskalWallis test. We used multivariate logistic regression to study the association of baseline UAE
(corrected for confounders measured at baseline) and impaired GFR. The response variable of
the logistic regression model was GFR < 60 mL/min/1.73 m2. The predictor variables
included in the regression model were UAE, gender, age, mean arterial pressure, BMI, plasma
glucose, serum cholesterol, smoking, the use of antihypertensive, lipid lowering or antidiabetic medication, and renal function at baseline. For optimal goodness of fit, UAE and
plasma glucose were transformed by a natural logarithm. A p-value of < 0.05 was considered
significant. Repeated analyses were performed after exclusion of subjects with cardiovascular
disease or diabetes at baseline. Analyses were also performed with GFR as calculated from
the MDRD formula.
Figure 1. Percentage of subjects with de novo renal function impairment for the categories of
UAE at baseline.
% subjects de novo renal impairment
30
25
20
15
10
5
n=4493
n=833
n=650
n=46
0
0-15
15-30
30-300
>300
Urinary albumin excretion (mg/24h) baseline
Albuminuria and impaired renal function
113
Results
Mean age at the baseline investigations was 48 years (SD 12) and GFR was 90.3 (SD 16.3)
mL/min/1.73 m2, as measured by the Cockcroft-Gault formula. The cohort contained 51.5%
men. Of the overall cohort, 696 (11.6%) subjects were newly diagnosed with an elevated
UAE. Of these, 650 had microalbuminuria and 46 had macroalbuminuria (UAE > 300
mg/24h). After a follow up of 4 years 253 subjects (4.2%) had developed a GFR < 60
mL/min/1.73 m2. Figure 1 shows an increasing prevalence of subjects with de novo renal
impairment over the various categories of baseline UAE. Subjects who developed de novo
renal impairment were older, had a lower GFR, higher blood pressure, plasma glucose, serum
cholesterol and UAE at the first screening than those who did not develop renal impairment
(table 1). More men had developed impaired renal function. Subjects with renal function
impairment were less often smokers compared to subjects with a GFR > 60. No difference in
BMI was observed.
Univariately, albuminuria was associated with de novo impaired renal function (table 2). After
gender and age adjustment the association was still significant. In addition, after correction for
the cardiovascular risk factors, albuminuria remained a predictor for renal function loss. The
impact of baseline albuminuria to predict de novo renal function impairment is also shown in
figure 2, which illustrates predicted odds ratio of a GFR < 60 according to UAE adjusted for
the confounders in the multivariate model. Exclusion of the subjects with cardiovascular
disease or diabetic patients did not influence the data significantly. Using MDRD estimated
GFR instead of Cockcroft-Gault estimated GFR, hardly changed the results of the
multivariate model.
Table 1. Population characteristics of subjects with normal GFR (> 60 mL/min/1.73 m2) at
baseline according to normal or impaired GFR at second screening.
Baseline characteristics
GFR second screening
P value
(mL/min/1.73 m2)
>60
<60
N
5769
253
Male gender (%)
51.1
60.5
0.003
Age (yrs)
47 (11)
65 (7)
<0.001
Mean arterial pressure (mmHg) 91.1 (11.7)
100.9 (13.2)
<0.001
Body mass index (kg/m2)
26.0 (4.1)
26.3 (3.5)
0.324
Cholesterol (mmol/L)
5.6 (1.1)
6.0 (1.2)
<0.001
Glucose (mmol/L)
4.8 (1.1)
5.4 (1.9)
<0.001
Smoking (%)
37.1
26.5
0.001
UAE (mg/24h)
8.7 (6.1-14.7)
13.5 (7.1-30.2) <0.001
GFR (mL/min/1.73 m2)
91.3 (15.8)
66.9 (6.5)
<0.001
The mean ± standard deviation is given, except for UAE, which is expressed as median
with the 25th and 75th percentiles.
114
Chapter 8
Table 2. Albuminuria as predictor for GFR < 60 mL/min/1.73 m2 after 4 year follow-up
(Logistic regression model).
Unadjusted
Age and gender adjusted Adjusted for confounders*
Odds Ratio
(95% CI) Odds Ratio
(95% CI) Odds Ratio
(95% CI)
Ln UAE 1.63
1.46-1.82 1.31
1.15-1.49 1.30
1.11-1.52
* Baseline GFR, age, gender, mean arterial blood pressure, body mass index, serum
cholesterol, plasma glucose, smoking, medication for hypertension, hypercholesterolaemia or
diabetes.
Figure 2. Adjusted predicted odds ratio of GFR < 60 versus UAE of 2 mg/24h. The dashed
lines indicate the 95% confidence interval. The gray area indicates the microalbuminuric
range (UAE 30-300 mg/24h).
10
9
8
Odds Ratio
7
6
5
4
3
2
1
0
1
10
100
1000
Urinary albumin excretion baseline (mg/24 h)
Albuminuria and impaired renal function
115
Discussion
We show that urinary albumin excretion is, also in the general population, predictive for the
development of de novo renal function impairment, independent of gender, age and
cardiovascular risk factors. Renal impairment is common in the general population. However,
it is usually asymptomatic and for that reason often not diagnosed. The Framingham Heart
Study (data collection 1977-1983) showed that 8.9% of men and 8.0% of women have
elevated serum creatinine levels (14). In the NHANES III (1988-1994) the prevalence of GFR
< 60 mL/min/1.73 m2 was 4.7% (8.3 million subjects) (15), and in the baseline screening of
our albuminuria enriched cohort 312 out of the 8592 (= 3.6%) subjects had a GFR below 60
mL/min/1.73 m2. Early detection of renal impairment and subsequent institution of
renoprotective treatment may lower the burden of ESRD and importantly, cardiovascular
morbidity and mortality (16). In diabetes, the evidence that microalbuminuria predicts renal
and cardiovascular complications resulted in diagnostic and therapeutic guidelines for clinical
practice. These guidelines advise to screen patients with diabetes yearly for the presence of
albuminuria (17). Therapeutical interventions that lower UAE delay the occurrence of renal
complications in diabetes (18). In hypertensive patients, a comparable link between
albuminuria and future renal and cardiac damage is highly likely (19-21), though screening
for microalbuminuria in hypertension is not yet a routine in clinical practice. The present
study shows that even in the general population UAE is predictive for de novo renal function
impairment. This finding might indicate that screening for albuminuria in the general
population could lead to an early detection of progressive renal function impairment.
A recently published study of the Framingham Heart Study described predictors of kidney
disease, as defined by sex-specific lowest five percent of MDRD estimated GFR (22). The
authors conclude that de novo renal impairment is predicted by baseline renal function, age
and cardiovascular risk factors. Our data add that in the general population albuminuria seems
to be a strong risk marker for the development of renal function impairment compared to the
classical cardiovascular risk factors.
Serum creatinine during follow-up was corrected because a systematic error was detected that
was introduced by a change in the analytical procedure. When this correction would not have
been applied the number of subjects developing a GFR < 60 mL/min/1.73 m2 was 479 (8.0%).
The results obtained however, would not be essentially different. Univariately and
multivariately urinary albumin excretion would still predict de novo renal function
impairment significantly: Odds ratio of Ln UAE for predicting a GFR < 60 mL/min/1.73 m2
unadjusted 1.47 (1.34–1.61), adjusted for age and gender 1.15 (1.02–1.28) and adjusted for
multiple confounders 1.25 (1.09–1.44). Our study is limited by the fact that the subjects
included in the analyses are by definition subjects that survived for four years. It is generally
accepted that both an increased UAE and diminished renal function are a risk factors or
indicators for (cardiovascular) mortality. For this reason the presented results may be an
underestimation. A second limitation is that we used a formula to estimate renal function
instead of directly measuring renal function.
We conclude that albuminuria is a strong predictor of diminished renal function de novo. The
risk attributed to albuminuria is furthermore independent from cardiovascular risk factors.
Albuminuria may therefore also in the general population prove to be a valuable risk marker
for future renal function decline amenable for screening purpose.
116
Chapter 8
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
Mogensen CE. Prediction of clinical diabetic nephropathy in IDDM patients. Alternatives to
microalbuminuria? Diabetes 1990;39(7):761-7.
Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset
diabetes. N.Engl.J.Med. 1984;310(6):356-60.
Jarrett RJ, Viberti GC, Argyropoulos A, Hill RD, Mahmud U, Murrells TJ. Microalbuminuria predicts
mortality in non-insulin-dependent diabetes. Diabet Med 1984;1:17-9.
Jensen T, Borch-Johnsen K, Kofoed-Enevoldsen A, Deckert T. Coronary heart disease in young type 1
(insulin-dependent) diabetic patients with and without diabetic nephropathy: incidence and risk factors.
Diabetologia 1987;30(3):144-8.
Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S, Schroll M, Jensen JS. Urinary albumin excretion.
An independent predictor of ischemic heart disease. Arterioscler.Thromb.Vasc.Biol. 1999;19(8):1992-7.
Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf B et al. Albuminuria and risk of
cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA
2001;286(4):421-6.
Hillege HL, Fidler V, Diercks GF, van Gilst WH, de Zeeuw D, van Veldhuisen DJ et al. Urinary
albumin excretion predicts cardiovascular and noncardiovascular mortality in general population.
Circulation 2002;106(14):1777-82.
Hillege HL, Janssen WM, Bak AA, Diercks GF, Grobbee DE, Crijns HJ et al. Microalbuminuria is
common, also in a nondiabetic, nonhypertensive population, and an independent indicator of
cardiovascular risk factors and cardiovascular morbidity. J.Intern.Med. 2001;249(6):519-26.
Bois du D, Bois du EF. A formula to estimate the approximate surface area if height and weight be
known. Arch.Int.Med. 1916;17:863-71.
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate
glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in
Renal Disease Study Group. Ann.Intern.Med. 1999;130(6):461-70.
Kidney Disease Outcomes Quality Initiative. Am.J.Kidney Dis. 2002;39(2):s17-s31.
Passing H, Bablok W. A new biometrical procedure for testing the equality of measurements from two
different analytical methods: application of linear regression procedures for method comparison studies
in clinical chemistry. Part I. J.Clin.Chem.Clin.Biochem. 1983;21:709-20.
Passing H, Bablok W. Comparison of several regression procedures for method comparison studies and
determination of sample sizes: application of linear regression procedures for method comparison
studies in clinical chemistry. Part II. J.Clin.Chem.Clin.Biochem. 1984;22:431-45.
Culleton BF, Larson MG, Evans JC, Wilson PW, Barrett BJ, Parfrey PS et al. Prevalence and correlates
of elevated serum creatinine levels: the Framingham Heart Study. Arch.Intern.Med. 1999;159(15):178590.
Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and
decreased kidney function in the adult US population: Third National Health and Nutrition Examination
Survey. Am.J.Kidney Dis. 2003;41(1):1-12.
Manjunath G, Tighiouart H, Ibrahim H, MacLeod B, Salem DN, Griffith JL et al. Level of kidney
function as a risk factor for atherosclerotic cardiovascular outcomes in the community.
J.Am.Coll.Cardiol. 2003;41(1):47-55.
Diabetic nephropathy, American Diabetes Association. Diabetes Care 2000;23 Suppl 1:S85-S89.
Tight blood pressure control and risk of macrovascular and microvascular complications in type 2
diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 1998;317(7160):703-13.
Bigazzi R, Bianchi S, Baldari D, Campese VM. Microalbuminuria predicts cardiovascular events and
renal insufficiency in patients with essential hypertension. J.Hypertens. 1998;16(9):1325-33.
Berrut G, Bouhanick B, Fabbri P, Guilloteau G, Bled F, Le Jeune JJ et al. Microalbuminuria as a
predictor of a drop in glomerular filtration rate in subjects with non-insulin-dependent diabetes mellitus
and hypertension. Clin.Nephrol. 1997;48(2):92-7.
Reid M, Bennett F, Wilks R, Forrester T. Microalbuminuria, renal function and waist:hip ratio in black
hypertensive Jamaicans. J.Hum.Hypertens. 1998;12(4):221-7.
Fox CS, Larson MG, Leip E.P., Culleton B, Wilson PWF, Levey D. Predictors of new-onset kidney
disease in a community-based population. JAMA 2004;291:844-50.